1. Field of the Invention
This invention relates to treatment of chemical ulcers, such as those caused by anthracyclines. More specifically, it concerns treatment of such ulcers with N,N'-Diacetylcystine, N-Acetyl Homocysteine and N-Acetyl Cysteine by interfering with leukotriene production.
2. General Background of the Invention
The anthracyclines have the general formula: ##STR1## and their essential structure is based on the anthraquinone ring which characteristically has a quinone functionality on the C ring and a hydroquinone function on the B ring. In addition, a hexose sugar is commonly attached through a glycosidic linkage at R.sub.3. Daunosamine is the most common sugar to be found at R.sub.3, R.sub.1, and R.sub.2, while R.sub.4 can vary widely. The two anthracyclines presently in clinical use are doxorubicin (marketed by Adria Laboratories of Dublin, Ohio as Adriamycin.TM.) and duanomycin. In doxorubicin, R.sub.1, R.sub.2, and R.sub.4 are H, OCH.sub.3, and OH; this structure is shown below: ##STR2## For duanomycin, R.sub.1, R.sub.2 and R.sub.4 are H,OCH.sub.3 and H, respectively, while R.sub.3 is daunosamine.
The anthracyclines are members of the Rhodomycin group of antibiotics produced by Streptomyces. The anthracyclines are o interest because a number of them show considerable activity against a wide range of human and animal tumors. Two members of this group, daunomycin and doxorubicin (Adriamycin.TM.), are in widespread use in this country as anticancer agents. However, the clinical use of these drugs is impaired because they cause cardiac damage in both man and animals.
Another important toxicity associated with these agents is tissue necrosis, often requiring surgical debridement if the agents extravasate into subcutaneous tissue during intravenous injections. This problem is particularly harmful and painful since these chemical ulcers tend to last many months and usually require surgical debridement.
A number of agents have been injected or topically applied to animal models or clinical cases of Adriamycin.TM. (ADM) skin necrosis. Sodium bicarbonate (Lancet, 2: 417, 1978), alpha tocopherol, beta adrengics, diphendydramine and cimetidine (Cancer Treat Rep. 65: 1001, 1981), DMSO (Cancer Treat Rep. 67: 407, 1983) and corticosteroids (Am. J. Nurs. 79: 94, 1979) have all been tried. For various reasons, none of these agents have been widely accepted.
N-acetylcysteine is an agent that has been extensively evaluated for all types of ADM toxicities. Unfortunately, previous reports have indicated that when NAC was injected intradermally just proximal to ADM induced ulcers in mice, the latter ulcers became worse (Cancer Treat. Rep. 65: 1001, 1981). With the exception of corticosteroids, surgical debridement and graft placement, there has been no satisfactory parenteral or topical formulation available for treating these chemical ulcers.
It is accordingly an object of this invention to provide a non-toxic, water soluble, tissue penetratable agent which is absorbed in effective amounts and that can promote tissue healing.